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The HDAC Inhibitor RM-3-22 Suppresses Triple-Negative Breast Cancer by Uncoupling Autophagy to Drive FSP1-Dependent
Essha Chatterjee1, Biswajit Dey1, Santanu Basak2
1Dept. of Biological Sciences, National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad, Telangana 500037, India; Dept. of Biotechnology and Bioinformatics, Sambalpur University, Jyoti Vihar, Burla, Odisha 768019, India.
Abstract:
Triple negative breast cancer (TNBC) remains one of the difficult subtypes to treat since it holds aggressiveness, a high recurrence rate, and is devoid of targeted therapy options. Taking these challenges into view, we developed RM-3-22, a hydroxamic acid-based histone deacetylase (HDAC) inhibitor, as a new therapeutic entity, particularly to target TNBC. Various experiments were performed using TNBC cell lines and a xenograft mouse model. Results revealed that RM-3-22 exhibited greater cytotoxicity than SAHA, an FDA-approved inhibitor with IC50 values of 6.49, 7.3, and 3.89 μM against MDA-MB-231, BT-549, and 4T1 Cells, respectively. RM-3-22 exhibited a strong anti-metastatic profile, as evidenced by impaired migratory capabilities of TNBC cells and significant disruption of the architecture of TNBC cell 3D spheroids. Furthermore, RM-3-22 suppressed TNBC progression by targeting autophagy and ferroptosis, as evidenced by reduced p62 and FSP1 expression and increased LC3B and ACSL4 expression. Our research explored the key axis where induction of autophagy is required for RM-3-22-mediated FSP1-dependent ferroptosis in the TNBC model. Surprisingly, as far as we know, this study is the first to show that HDAC inhibitors could induce autophagy-dependent ferroptosis as a cell death mechanism to halt TNBC progression. These results were further validated by the effective reduction in tumour growth in the xenograft mouse model. Collectively, RM-3-22 could be a promising alternative inhibitor for TNBC by targeting the autophagy-ferroptosis mechanism(s).
Insights
A novel histone deacetylase (HDAC) inhibitor, RM-3-22, effectively targets triple-negative breast cancer (TNBC) by inducing autophagy-dependent ferroptosis, offering a new therapeutic strategy for this aggressive cancer subtype.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapies.
- Histone deacetylase (HDAC) inhibitors represent a potential therapeutic avenue.
Purpose of the Study:
- To develop and evaluate RM-3-22, a novel HDAC inhibitor, as a targeted therapy for TNBC.
- To investigate the mechanism of action of RM-3-22 in TNBC, focusing on autophagy and ferroptosis.
Main Methods:
- In vitro cytotoxicity assays using TNBC cell lines (MDA-MB-231, BT-549, 4T1).
- Assessment of anti-metastatic effects on TNBC cell migration and spheroid architecture.
- Analysis of protein expression related to autophagy (LC3B, p62) and ferroptosis (FSP1, ACSL4).
- In vivo efficacy studies using a TNBC xenograft mouse model.
Main Results:
- RM-3-22 demonstrated superior cytotoxicity compared to SAHA in TNBC cell lines.
- RM-3-22 significantly inhibited TNBC cell migration and disrupted spheroid structure.
- RM-3-22 modulated autophagy and ferroptosis pathways, indicated by altered protein expression (reduced p62/FSP1, increased LC3B/ACSL4).
- RM-3-22 effectively reduced tumor growth in a xenograft mouse model.
Conclusions:
- RM-3-22 is a potent HDAC inhibitor with significant anti-TNBC activity.
- The study reveals a novel mechanism of autophagy-dependent ferroptosis induced by HDAC inhibitors in TNBC.
- RM-3-22 shows promise as a new therapeutic agent for TNBC by targeting the autophagy-ferroptosis axis.
